Content area
Full Text
Introduction
Cancer is the leading cause of death worldwide, accounting for 8.2 billion deaths in 2012 alone (1). Multimodal treatment, including chemotherapy, surgery, and radiotherapy, has dramatically reduced cancer mortality and improved the quality of life of individuals with cancer (1–3). However, not all patients respond positively to currently available therapies, and relapse is common in patients who initially respond to chemotherapy. The epithelial-mesenchymal transition (EMT) is an essential mechanism involved in tumor progression and metastasis, and the tumor microenvironment, including the extracellular matrix and numerous stromal cell types, has been shown to induce EMT (4,5). Therefore, the development of novel treatments targeting the EMT process may provide effective therapies for patients who do not respond to current treatments or who experience chemoresistant relapse.
Platelets, the smallest anucleate hematopoietic cells, are now recognized as key regulators of tumor progression and metastasis (6–8). In the circulation, platelet aggregation protects cancer cells from shear stress and immune surveillance through the formation of a platelet cloak. Platelets also facilitate cancer cell adherence to vascular endothelial cells, which leads to extravasation into the stroma and the formation of secondary tumors (9). However, the presence and role of platelets in primary tumors are not well understood.
Platelets contain numerous platelet-derived growth mediators and cytokines related to EMT, such as transforming growth factor-β (TGF-β), vascular endothelial growth factor-A (VEGF-A), and plasminogen activator inhibitor-1 (PAI-1). Labelle et al reported that direct signaling between platelets and breast cancer cells in the vasculature induces the latter to undergo EMT (10). Furthermore, investigations have demonstrated that tumors undergoing EMT show increased resistance to chemotherapy (11,12). Moreover, in a study targeting chemoresistant breast cancer cells following neo-adjuvant chemotherapy, we found that some patients achieved pathological complete response (pCR; defined as no residual invasive cancer in the breast and lymph nodes), which would be expected to be associated with a more favorable prognosis than that in patients who did not achieve pCR (13). Chemoresistance involves numerous complex mechanisms, including gene pathways associated with apoptosis/senescence and DNA repair, which are often influenced by communication between host and tumor cells (14). Furthermore, EMT, anti-apoptotic mechanisms, and stemness induced by the cancer microenvironment have been shown to play important roles in chemoresistance (15).
Therefore, we hypothesized that platelets surrounding tumor...